Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
Nat Cell Biol. 2020 Oct;22(10):1252-1263. doi: 10.1038/s41556-020-00583-9. Epub 2020 Sep 28.
Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
溶酶体功能失调的感应和清除对于细胞稳态至关重要。在这里，我们表明转录因子 EB（TFEB）——溶酶体生物发生和自噬的主要转录调节剂——在溶酶体损伤反应中被激活，其激活依赖于 ATG 连接系统的功能，该系统介导 LC3 脂质化。此外，溶酶体损伤触发 LC3 在溶酶体上的募集，其中脂质化的 LC3 与溶酶体钙通道 TRPML1 相互作用，促进钙外排，这对于 TFEB 的激活是必不可少的。此外，我们在草酸肾病伴随溶酶体损伤的小鼠模型中证明了这种 TFEB 激活机制在肾脏中的存在和重要性。近端小管特异性 TFEB 敲除小鼠表现出草酸晶体诱导的肾脏损伤的进展。总之，我们的结果揭示了 LC3 脂质化激活 TFEB 的意想不到的机制及其在溶酶体损伤反应中的生理相关性。
